Our studies of adult immune reconstitution have demonstrated that severe deficits in naive T cells and TCR repertoire develop and persist in older patients with limited renewal of thymopoiesis. In order to develop IL-7 as a potential therapeutic agent to enhance nave populations in these patients, we initiated the first phase I study of recombinant human IL-7 (rhIL-7) administration in humans. We showed that rhIL-7 has the potential to induce thymic-independent T-cell expansion in naive and CM populations and enhance repertoire diversity in peripheral T-cell populations. Whether this repair of repertoire is of functional importance is being addressed in a new clinical trial which is no longer delayed pending a source of clinical grade IL-7. A new source has been identified and a new study is being written with near completion of the final draft. We also initiated a clinical trial to treat the pulmonary complication of chronic graft versus host disease known as bronchiolitis obliterans. Results were encouraging and led to a national multi-center trial. Together, the results have changed the general care of patients with this pulmonary complication of allogeneic transplant. A trial treating leukemia with myeloablative therapy and assessing improvement in immune reconstitution by modulation of thymus function by temporary blockade of androgen signaling is completed with lab results under study. In a trial involving unrelated donor allogeneic peripheral blood stem cell transplantation, we have developed an extensive, clinically annotated data base of laboratory values relevant to immune reconstitution. This data set has shown that steroid therapy has little immediate effect on T cell numbers and confirms our data on expansion of CD8+ T cells associated with CMV infection. We have used cells and tissue biopsies from this trial to prospectively study the pathogenesis of chronic graft-versus host disease and found that it a Type I driven (not Type II as has been thought) process. These results are now published. We are seeking new therapies for this complication of allogeneic transplant based on this new understanding. At this point it appears that introduction of such therapy may await approval of such agents for other indications. In another trial assessing the feasibility of imaging the hematopoietic stem cell compartment during engraftment, it was found that such imaging is feasible and also quantifiable, so that applicability to settings of radiation injury may be possible. That is, subjects of such injury may be identified as needing intervention with hematopoietic stem cell rescue or not. We have gained access to a new source for IL-7. The previous study showed enhanced immune reconstitution with the surprising finding of re-diversification of the T cell repertoire without involvement of renewed thymus function. The next step is to investigate whether that renewed repertoire results in better T cell mediated immune response. The clinical protocol, then, is written to assess response to vaccines with and without IL-7. The study is written and under review.